Project Summary/Abstract At present, tissue-type plasminogen activator (tPA) is the only FDA approved stroke therapy. tPA establishes reperfusion by thrombolysis of clots, but only a small subset of patients is eligible for tPA therapy. Moreover, the brain damage that occurs before and after tPA therapy is still an unmet clinical need. Identifying new therapeutic targets helps in developing novel and potent drugs to curtail post-stroke secondary brain damage. Our recent studies have shown that elevation of matrix metalloproteinase-12 (MMP-12) during reperfusion following transient focal ischemia in rodents contributes to BBB damage, apoptosis, and brain infarction. We currently hypothesize that the induction of MMP-12 contributes to post-stroke pathophysiology and compromises the neurologic outcome. Aim 1 is to characterize the role of MMP-12 in post-stroke brain damage and neurological recovery in both males and females as well as in a second species. Aim 2 is to unravel the source of MMP-12 and elucidate the molecular mechanisms underlying MMP-12-induced brain damage after stroke. Aim 3 is to investigate the efficacy of post-ischemic MMP-12 suppression in aged animals and animals with hypertension. We will use state of the art techniques including the shRNA-mediated knockdown of target genes by nanoparticle-mediated delivery of plasmids, suture model middle cerebral artery occlusion procedure, FACS analysis, and transmission electron microscopy to execute the proposed experiments. The long-term goal of this project is to develop post-stroke therapies that modulate MMP-12 to prevent secondary brain damage and promote neurological recovery.